The aim of this study is to investigate selected areas of the neurobiology of depression and mania. In previous studies, we have observed that abnormality of noradrenergic and HPA axis dysfunction occur together in seriously depressed patients. We have pursued the study of the role of corticosteroids in depressive illness by examining the effect of exogenous steroid administration. We have found that orally administered dexamethasone produces selective effects on catecholamine function in depressed patients; in contrast to normal controls, depressed patients, particularly those with psychotic features, showed a significant dexamethasone-induced increase in plasma MHPG and a decrease in plasma HVA. These data suggesting abnormal corticosteroid-catecholamine interactions in depression are consistent with the possibility that hypercortisolemia itself may produce or enhance some of the biochemical changes and/or behavioral signs of depression. In a double-blind study of orally administered prednisone (80 mg/day x 5 days) to normal volunteers, we have further investigated steroid effects on the central nervous system. The relationship between stress, steroids, and mood, has been pursued in an experiment in which identical amounts of escapable and inescapable aversive noise stimuli are presented to subjects. Preliminary results suggest that inescapable but not escapable "stress" produces correlated mood and neuroendocrine response. We have examined the effects of permanent separation from one or both biological parent(s) between the ages of 2 and 17 years on the development of adult psychopathology and observed that poorer quality of home life and personal adaptation subsequent to parental loss was associated with significantly higher incidence of major depression as adults and increased levels of plasma cortisol at the time of cross- sectional study. We are currently investigating the therapeutic and biochemical effects of verapamil, a calcium channel antagonist, in manic and hypomanic patients.